A second-generation hepatitis C protease inhibitor, faldaprevir,
cured up to 80% of previously untreated people with genotype 1 hepatitis C virus (HCV)
infection when combined with pegylated interferon and ribavirin, Professor
Peter Ferenci of the Medical University of Vienna reported on Saturday at the
International Liver Congress (EASL 2013) in Amsterdam.
The findings came from the phase III STARTVerso study which
randomised 656 people with chronic hepatitis C infection to receive at least 12
weeks of faldaprevir or placebo, in combination with pegylated interferon and
The results of STARTVerso, together with two other phase
III study results, are likely to be submitted later this year to support the licensing of
faldaprevir in the United States and European Union. Faldaprevir is being
developed by Boehringer-Ingelheim for use with pegylated interferon and
ribavirin, and also for use in interferon-free regimens.
Speaking at a press conference on the opening day of the
International Liver Congress, EASL Secretary-General Prof. Mark Thursz said
that he expected faldaprevir, another second-generation protease inhibitor
simeprevir, and sofosbuvir, a NS5B nucleotide polymerase inhibitor, to “totally
cannibalise” the market niche for hepatitis C therapy currently occupied by the
first-generation protease inhibitors boceprevir (Victrelis) and telaprevir (Incivo).
STARTVerso randomised participants to receive one of two
doses of faldaprevir (120mg once daily or 240mg once daily) or placebo for at
least 12 weeks, in combination with pegylated interferon and ribavirin.
At 12 weeks, participants in the 120mg arm were randomised to
continue faldaprevir treatment to week 24, or to a placebo, and all participants
continued pegylated interferon and ribavirin to week 24. At week 24, people
who had achieved HCV RNA <25 IU/ml at week 4 and HCV RNA <25 IU/ml and
undetectable at week 8 (Early Treatment Success) were eligible to stop all
treatment. The remainder received pegylated interferon and ribavirin to week
In the 240mg arm, all participants stopped faldaprevir at
week 12 but continued pegylated interferon and ribavirin to week 24. All
participants in this arm who achieved Early Treatment Success (ETS) were able
to stop treatment at week 24. The remainder received pegylated interferon and
ribavirin to week 48.
In the control arm, all participants received pegylated
interferon and ribavirin plus placebo for 24 weeks, followed by a further 24
weeks of pegylated interferon and ribavirin.
Depending on their treatment assignment, up to 80% of
people who received faldaprevir achieved a sustained virologic response 12
weeks after stopping treatment (SVR12). There was no difference in efficacy between the
two doses of faldaprevir but the lower dose (120mg) was better tolerated.
Around two-thirds of study participants had genotype 1b
hepatitis C infection.Between 58 and 65% had a CT or TT IL28B genotype,
indicating the likelihood of a poorer response to interferon-based treatment.
Participants were predominantly Caucasian (78%) and in the earlier stages of
liver disease (METAVIR score F1-F2) (81-84%) according to study arm. Six per
cent of participants had cirrhosis.
Final results showed that by intent-to-treat analysis 80% of
patients in the faldaprevir 240mg arm and 79% in the 120mg arm achieved SVR12,
compared with 52% in the pegylated interferon/ribavirin arm (p< 0.001).
A total of 88% achieved early treatment success and were
eligible to stop all treatment at week 24. Of these patients 89% in the 240mg
group and 86% in the 120mg group achieved SVR12. There was a pronounced difference in SVR rates in the
faldaprevir-treated patients between those with detectable or undetectable HCV
RNA at week 4. Among those with HCV RNA below the limit of quantification but
still detectable at week 4, 77% in the 120mg and 72% in the 240mg achieved SVR12. Among those with undetectable HCV RNA at week 12, 91 and 94% respectively
There was a modest difference in response rates between HCV
genotype 1a and 1b in the faldeparevir 240mg group (76 vs 83%) favouring
genotype 1b. The difference was more pronounced in the faldaprevir 120mg group
(69 vs 84%). This difference in SVR12 rates was not explained by higher rates
of null or partial response, but by higher rates of viral breakthrough during
treatment and post-treatment viral relapse.
Responses also differed according to IL28B genotype. Those
with the favourable CC genotype had the best responses (90 and 95% in the
120mg and 240mg groups respectively), compared to 70 and 69% for those with
the CT genotype and 76 and 79% for the TT genotype.
Adverse events leading to treatment discontinuation occurred
in 4% of placebo recipients, 4% of faldaprevir 120mg recipients and 5% of
faldeprevir 240mg recipients. Serious adverse events occurred in 7% of
faldaprevir recipients. The only adverse events that occurred more frequently
in faldaprevir-treated patients were gastrointestinal, and these occurred with
highest frequency in the 240mg group.
12% of these patients experienced gastrointestinal symptoms
compared with 7% in the faldaprevir 120mg group and 3% in the control group who
were taking pegylated interferon and ribavirin with placebo.
Mild to moderate rash was also observed in more patients
taking faldaprevir compared with the placebo group. 32-33% of patients taking
120mg or 240 mg faldaprevir respectively experienced rash, compared with 22% in
the placebo group. Severe rash was rarely observed, occurring in two patients in each
study arm (6 cases overall). None of the rash events observed in this trial were
life-threatening, and all events resolved.
A higher frequency of jaundice in faldaprevir-treated
patients (3% in the 240mg group) was accompanied by a higher frequency of
bilirubin elevations (53% of patients in the 240mg group experienced bilirubin
elevations, compared to 12% in the 120mg group). These increases were transient
and bilirubin levels returned to normal after week 16.
There was no difference in the incidence of anaemia between
the study arms up to week 24. People in the faldaprevir arms were less likely
to require ribavirin dose reductions.
The 240mg dose offered no clear advantages over the 120mg
dose, Professor Ferenci concluded, although the finding of lower response rates
in genotype 1a in the 120mg dose group may leave that conclusion open to